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CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer

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submitted on 2024-05-26, 06:01 and posted on 2024-05-26, 06:02 authored by Lei Nie, Yongkun Wei, Fei Zhang, Yi-Hsin Hsu, Li-Chuan Chan, Weiya Xia, Baozhen Ke, Cihui Zhu, Rong Deng, Jun Tang, Jun Yao, Yu-Yi Chu, Xixi Zhao, Ye Han, Junwei Hou, Longfei Huo, How-Wen Ko, Wan-Chi Lin, Hirohito Yamaguchi, Jung-Mao Hsu, Yi Yang, Dean N. Pan, Jennifer L. Hsu, Celina G. Kleer, Nancy E. Davidson, Gabriel N. Hortobagyi, Mien-Chie Hung

Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.

Other Information

Published in: Nature Communications
License: https://creativecommons.org/licenses/by/4.0
See article on publisher's website: https://dx.doi.org/10.1038/s41467-019-13105-5

Funding

Open Access funding provided by the Qatar National Library.

History

Language

  • English

Publisher

Springer Nature

Publication Year

  • 2019

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • Qatar Biomedical Research Institute - HBKU
  • Cancer Research Center - QBRI